Process for preparation of isosulfan blue

Abstract

A process for the preparation of isosulfan blue (Active Pharmaceutical Ingredient) is provided. A process is also provided for preparation of the intermediate, 2-chlorobenzaldehyde-5-sulfonic acid, sodium salt of formula (2), used in the preparation thereof and a procedure for the isolation of benzaldehyde-2,5-disulfonic acid, di-sodium salt of the formula (3). Also provided is a process for the preparation of an isoleuco acid of formula (4), which upon mild oxidation gives rise to isosulfan blue of pharmaceutical grade which can be used for preparation of pharmaceutical formulations. The isolation and purification procedures provided in the process provide substantially pure isosulfan blue with HPLC purity 99.5% or greater.

The invention claimed is: 
     
       1. A compound N-[4-[[4-(diethyl amino)phenyl](2,5-disulfophenyl)methylene]-2,5-cyclohexadien-1-ylidene]-N-ethylethanaminium, sodium salt having a purity of at least 99.0% by HPLC. 
     
     
       2. The compound according to  claim 1  having a purity between 99.0% and 99.5% by HPLC. 
     
     
       3. The compound according to  claim 1  having less than 20 ppm silver. 
     
     
       4. The compound according to  claim 3  having a purity greater than 99.5% by HPLC. 
     
     
       5. The compound according to  claim 1  prepared by a process comprising combining a suspension of isoleuco acid of the formula 
       
         
           
           
               
               
           
         
       
       in a polar solvent with silver oxide, recovering isosulfan blue acid, and treating the isosulfan blue acid with a sodium solution. 
     
     
       6. The compound according to  claim 5  wherein the process comprises sulfonation of 2-chlorobenzaldehyde to obtain 2-chlorobenzaldehyde-5-sulfonic acid sodium salt of the formula 
       
         
           
           
               
               
           
         
       
       followed by nucleophilic displacement of the chloride in 2-chlorobenzaldehyde-5-sulfonic acid sodium salt with an alkali metal sulfite and bisulfate to obtain benzaldehyde-2,5-disulfonic acid, disodium salt of the formula 
       
         
           
           
               
               
           
         
       
       and condensing the benzaldehyde-2,5-disulfonic acid, disodium salt of the formula (3) with N, N-diethylaniline using urea and glacial acetic acid to provide isoleuco acid of the formula (4). 
     
     
       7. The compound according to  claim 6  wherein the process of preparing 2-chlorobenzaldehyde-5-sulfonic acid, sodium salt of formula (2) comprises reacting 2-chlorobenzaldehyde with sulfuric acid. 
     
     
       8. The compound according to  claim 5  wherein the polar solvent is methanol. 
     
     
       9. The compound according to  claim 5  wherein the isoleuco acid of the formula 
       
         
           
           
               
               
           
         
       
       is prepared by combining a benzaldehyde-2,5-disulfonic acid, disodium salt of the formula 
       
         
           
           
               
               
           
         
       
       with N, N-diethylaniline, and urea and glacial acetic acid. 
     
     
       10. The compound according to  claim 5  wherein the process comprises recrystallization of N-[4-[[4-(diethylamino)phenyl](2,5-disulfophenyl)methylene]-2,5-cyclohexadien-1-ylidene]-N-ethylethanaminium using a solvent selected from the group consisting of a polar solvent, a non-polar solvent and a combination thereof to afford HPLC purity greater than 99.5%. 
     
     
       11. A solution containing N-[4-[[4-(diethyl amino)phenyl](2,5-disulfophenyl)methylene]-2,5-cyclohexadien-1-ylidene]-N-ethylethanaminium, sodium salt, the N-[4-[[4-(diethyl amino)phenyl](2,5-disulfophenyl)methylene]-2,5-cyclohexadien-1-ylidene]-N-ethylethanaminium, sodium salt having a purity of at least 99.0% by HPLC. 
     
     
       12. The solution according to  claim 11  wherein the N-[4-[[4-(diethyl amino)phenyl](2,5-disulfophenyl)methylene]-2,5-cyclohexadien-1-ylidene]-N-ethylethanaminium, sodium salt has a purity between 99.0% and 99.5% by HPLC. 
     
     
       13. The solution according to  claim 11  having less than 20 ppm silver. 
     
     
       14. The solution according to  claim 13  wherein the N-[4-[[4-(diethyl amino)phenyl](2,5-disulfophenyl)methylene]-2,5-cyclohexadien-1-ylidene]-N-ethylethanaminium, sodium salt has a purity greater than 99.5% by HPLC. 
     
     
       15. A composition consisting essentially of N-[4-[[4-(diethyl amino)phenyl](2,5-disulfophenyl)methylene]-2,5-cyclohexadien-1-ylidene]-N-ethylethanaminium, sodium salt, the N-[4-[[4-(diethyl amino)phenyl](2,5-disulfophenyl)methylene]-2,5-cyclohexadien-1-ylidene]-N-ethylethanaminium, sodium salt having a purity of at least 99.0% by HPLC. 
     
     
       16. The composition according to  claim 15  wherein the N-[4-[[4-(diethyl amino)phenyl](2,5-disulfophenyl)methylene]-2,5-cyclohexadien-1-ylidene]-N-ethylethanaminium, sodium salt has a purity between 99.0% and 99.5% by HPLC. 
     
     
       17. The composition according to  claim 15  having less than 20 ppm silver. 
     
     
       18. The composition according to  claim 17  wherein the N-[4-[[4-(diethyl amino)phenyl](2,5-disulfophenyl)methylene]-2,5-cyclohexadien-1-ylidene]-N-ethylethanaminium, sodium salt has a purity greater than 99.5% by HPLC.